title: Binge alcohol drinking is associated with GABAA alpha2-regulated Toll-like receptor 4 (TLR4) expression in the central amygdala.
abstract: Binge drinking (blood-alcohol levels ≥ 0.08 g% in a 2-h period), is a significant public health burden in need of improved treatment. Gene therapy may offer beneficial alternatives to current psychosocial and pharmacotherapeutic interventions, but identification of the target genes is a clinical challenge. We report that a GABA(A) α2 siRNA vector (pHSVsiLA2) infused into the central nucleus of the amygdala (CeA) of alcohol-preferring (P) rats caused profound and selective reduction of binge drinking associated with inhibition of α2 expression, decreased GABA(A) receptor density, and inhibition of Toll-like receptor 4 (TLR4). CeA infusion of a TLR4 siRNA vector (pHSVsiLTLR4a) also inhibited binge drinking, but neither vector functioned when infused into the ventral pallidum. Binge drinking was inhibited by a GABA(A) α1 siRNA vector (pHSVsiLA1) infused into the ventral pallidum, unrelated to TLR4. The vectors did not alter sucrose intake and a scrambled siRNA vector was negative. The data indicate that GABA(A) α2-regulated TLR4 expression in the CeA contributes to binge drinking and may be a key early neuroadaptation in excessive drinking.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Neuropsychopharmacology Laboratory, Division of Alcohol and Drug Abuse, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Yang
authors.forename: Timothy
authors.initials: T
authors.lastname: Kelly
authors.forename: Adam
authors.initials: A
authors.lastname: Puche
authors.forename: Chioma
authors.initials: C
authors.lastname: Esoga
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elnabawi
authors.forename: Istvan
authors.initials: I
authors.lastname: Merchenthaler
authors.forename: Werner
authors.initials: W
authors.lastname: Sieghart
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
authors.forename: Laure
authors.initials: L
authors.lastname: Aurelian
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000679:Amygdala / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005822:Genetic Vectors; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C520011:Gabra2 protein, rat; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4